title: Sodium accumulation is associated with disability and a progressive course in multiple sclerosis.
abstract: Neuroaxonal loss is a major substrate of irreversible disability in multiple sclerosis, however, its cause is not understood. In multiple sclerosis there may be intracellular sodium accumulation due to neuroaxonal metabolic dysfunction, and increased extracellular sodium due to expansion of the extracellular space secondary to neuroaxonal loss. Sodium magnetic resonance imaging measures total sodium concentration in the brain, and could investigate this neuroaxonal dysfunction and loss in vivo. Sodium magnetic resonance imaging has been examined in small cohorts with relapsing-remitting multiple sclerosis, but has not been investigated in patients with a progressive course and high levels of disability. We performed sodium magnetic resonance imaging in 27 healthy control subjects, 27 patients with relapsing-remitting, 23 with secondary-progressive and 20 with primary-progressive multiple sclerosis. Cortical sodium concentrations were significantly higher in all subgroups of multiple sclerosis compared with controls, and deep grey and normal appearing white matter sodium concentrations were higher in primary and secondary-progressive multiple sclerosis. Sodium concentrations were higher in secondary-progressive compared with relapsing-remitting multiple sclerosis in cortical grey matter (41.3 ± 4.2 mM versus 38.5 ± 2.8 mM, P = 0.008), normal appearing white matter (36.1 ± 3.5 mM versus 33.6 ± 2.5 mM, P = 0.018) and deep grey matter (38.1 ± 3.1 mM versus 35.7 ± 2.4 mM, P = 0.02). Higher sodium concentrations were seen in T₁ isointense (44.6 ± 7.2 mM) and T1 hypointense lesions (46.8 ± 8.3 mM) compared with normal appearing white matter (34.9 ± 3.3 mM, P < 0.001 for both comparisons). Higher sodium concentration was observed in T₁ hypointense lesions in secondary-progressive (49.0 ± 7.0 mM) and primary-progressive (49.3 ± 8.0 mM) compared with relapsing-remitting multiple sclerosis (43.0 ± 8.5 mM, P = 0.029 for both comparisons). Independent association was seen of deep grey matter sodium concentration with expanded disability status score (coefficient = 0.24, P = 0.003) and timed 25 ft walk speed (coefficient = -0.24, P = 0.01), and of T1 lesion sodium concentration with the z-scores of the nine hole peg test (coefficient = -0.12, P < 0.001) and paced auditory serial addition test (coefficient = -0.081, P < 0.001). Sodium concentration is increased within lesions, normal appearing white matter and cortical and deep grey matter in multiple sclerosis, with higher concentrations seen in secondary-progressive multiple sclerosis and in patients with greater disability. Increased total sodium concentration is likely to reflect neuroaxonal pathophysiology leading to clinical progression and increased disability.
authors.affiliation: NMR Research Unit, Department of Neuroinflammation, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. d.paling@ucl.ac.uk
authors.forename: David
authors.initials: D
authors.lastname: Paling
authors.forename: Bhavana S
authors.initials: BS
authors.lastname: Solanky
authors.forename: Frank
authors.initials: F
authors.lastname: Riemer
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Tozer
authors.forename: Claudia A M
authors.initials: CA
authors.lastname: Wheeler-Kingshott
authors.forename: Raju
authors.initials: R
authors.lastname: Kapoor
authors.forename: Xavier
authors.initials: X
authors.lastname: Golay
authors.forename: David H
authors.initials: DH
authors.lastname: Miller
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004185:Disability Evaluation; D006233:Persons with Disabilities; D018450:Disease Progression; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D012964:Sodium / Q000378:metabolism*; D012975:Sodium Isotopes; D013223:Statistics as Topic; D055815:Young Adult
chemical_list: D012975:Sodium Isotopes; D012964:Sodium
keywords: MRI; Na+ channel; disability; disease progression; multiple sclerosis